Heterocyclic compounds

ABSTRACT

The present invention relates to novel N-substituted amino alcohols, amino acids and acid derivatives thereof in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation.

FIELD OF THE INVENTION

The present invention relates to novel N-substituted amino alcohols,amino acids and acid derivatives thereof in which a substituted alkylchain forms part of the N-substituent or salts thereof, to methods fortheir preparation, to compositions containing them, and to their use forthe clinical treatment of painful, hyperalgesic and/or inflammatoryconditions in which C-fibers play a pathophysiological role by elicitingneurogenic pain or inflammation.

The invention also relates to the use of the present compounds for thetreatment of insulin resistance in non-insulin-dependent diabetesmellitus (NIDDM) or ageing, the present compounds knowing to interferewith neuropeptide containing C-fibres and hence inhibit the secretionand circulation of insulin antagonizing peptides like CGRP or amylin.

BACKGROUND OF THE INVENTION

The nervous system exerts a profound effect on the inflammatoryresponse. Antidromic stimulation of sensory nerves results in localizedvasodilation and increased vascular permeability (Janecso et al. Br. J.Pharmacol. 1967, 31, 138-151) and a similar response is observedfollowing injection of peptides known to be present in sensory nerves.From this and other data it is postulated that peptides released fromsensory nerve endings mediate many inflammatory responses in tissueslike skin, joint, urinary tract, eye, meninges, gastro-intestinal andrespiratory tracts. Hence inhibition of sensory nerve peptide releaseand/or activity, may be useful in treatment of, for example arthritis,dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlebitis,glaucoma, gastro-intestinal diseases or migraine.

Further, the potent effects of CGRP on skeletal muscle glycogen synthaseactivity and muscle glucose metabolism, together with the notion thatthis peptide is released from the neuromuscular junction by nerveexcitation, suggest that CGRP may play a physiological role in skeletalmuscle glucose metabolism by directing the phosphorylated glucose awayfrom glycogen storage and into the glycolytic and oxidative pathways(Rossetti et al. Am. J. Physiol. 264, E1-E10, 1993). This peptide mayrepresent an important physiological modulator of intracellular glucosetrafficking in physiological conditions, such as exercise, and may alsocontribute to the decreased insulin action and skeletal muscle glycogensynthase in pathophysiological conditions like NIDDM orageing-associated obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995)where circulating plasma levels of CGRP are markedly increased. Henceinhibition of release and/or activity of the neuropeptide CGRP may beuseful in the treatment of insulin resistance related to type 2 diabetesor ageing.

In U.S. Pat. No. 4,383,999 and No. 4,514,414 and in EP 236342 as well asin EP 231996 some derivatives ofN-(4,4-disubstituted-3-butenyl)azaheterocyclic carboxylic acids areclaimed as inhibitors of GABA uptake. In EP 342635 and EP 374801,N-substituted azaheterocyclic carboxylic acids in which an oxime ethergroup and vinyl ether group forms part of the N-substituent respectivelyare claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO9220658, N-substituted azacyclic carboxylic acids are claimed as GABAuptake inhibitors. EP 221572 claims that1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.

In DE 2833892 some 12H-dibenzo d,g! 1,3,6!dioxozocine derivatives areclaimed as local anaesthetics or for treatment of parkinsonism.

DESCRIPTION OF THE INVENTION

The present invention relates to novel N-substituted amino alcohols,amino acids and acid derivatives thereof of formula I ##STR1## whereinR¹ and R² independently are hydrogen, halogen, trifluoromethyl, hydroxy,

C₁₋₆ -alkyl or C₁₋₆ -alkoxy; and

R³ is hydrogen or C₁₋₃ -alkyl; and

A is C₁₋₃ -alkylene; and

Y is >CH-CH₂ -, >C=CH-, >CH-O-, >C=N-, >N-CH₂ - wherein only theunderscored atom participates in the ring system; and

Z is selected from ##STR2## wherein n is 1 or 2; and R¹¹ is hydrogen orC₁₋₆ alkyl; and

R¹² is hydrogen, C₁₋₆ -alkyl, C₁₋₆ -alkoxy: and

methyl, hydroxy, C₁₋₆ alkyl or C₁₋₆ -alkoxy; and

R¹³ is hydrogen, halogen, trifluoromethyl, hydroxy, C₁₋₆ alkyl or C₁₋₆-alkoxy; and

R¹⁴ is -(CH₂)_(m) OH or -(CH₂)_(t) COR¹⁵ wherein m is 0, 1, 2, 3, 4, 5or 6 and t is 0 or 1 and

wherein R¹⁵ is -OH, NH₂, -NHOH or C₁₋₆ -alkoxy; and

R¹⁶ is C₁₋₆ -alkyl or -B-COR¹⁵, wherein B is C₁₋₆ alkylene, C₂₋₆-alkenylene or C₂₋₆ -alkynylene and

R¹⁵ is he same as above; and

. . is optionally a single bond or a double bond;

or a pharmaceutically acceptable salt thereof.

The compounds of formula I may exist as geometric and optical isomersand all isomers and mixtures thereof are included herein. Isomers may beseparated by means of standard methods such as chromatographictechniques or fractional crystallisation of suitable salts.

Preferably, the compounds of formula I exist as the individual geometricor optical isomers. The compounds according to the invention mayoptionally exist as pharmaceutically acceptable acid addition saltsor--when the carboxylic acid group is not esterified--aspharmaceutically acceptable metal salts or--optionallyalkylated-ammonium salts.

Examples of such salts include inorganic and organic acid addition saltssuch as hydrochloride, hydrobromide, sulphate, phosphate, acetate,fumarate, maleate, citrate, lactate, tartrate, oxalate or similarpharmaceutically acceptable inorganic or organic acid addition salts,and include the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) which are hereby incorporated byreference.

The term "C₁₋₆ -alkyl" as used herein, alone or in combination, refersto a straight or branched, saturated hydrocarbon chain having 1 to 6carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl,2,2-dimethylpropyl and 1,2,2-trimethylpropyl.

The term "C₁₋₆ -alkoxy" as used herein, alone or in combination, refersto a straight or branched monovalent substituent comprising a Cl.₆-alkyl group linked through an ether oxygen having its free valence bondfrom the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy,ethoxy, propoxy, isopropoxy, butoxy, pentoxy.

The term "halogen" means fluorine, chlorine, bromine or iodine.

Illustrative examples of compounds encompassed by the present inventioninclude:

2-Chloro-12-(3-dimethylamino)propylidene- 12H-dibenzo d,g! 1,3!dioxocine

2, 10-Dichloro-12-(2dimethylamino)ethoxy-12H-dibenzo d,g! 1,3!dioxocine.

2, 10-Dichloro-12-(3dimethylamino)propyl-12H-dibenzo d,g! l,3!dioxocine

2, 10-Dichloro-12-(3-dimethylamino-1-methyl)ethoxy-12H-dibenzo d,g!1,3!dioxocine

3-Chloro-12-(2-dimethylaminopropylidene)-12H-dibenzo d,g! 1,3!dioxocine

3-Chloro-12-(3-dimethylamino)propylidene-12dibenzo d,g! 1,3!dioxocine

3-Chloro-12-(3-dimethylamino-1-methylpropylidene)-12-H-dibenzo- d,g! 1,3!dioxocine

2-Fluoro-12-(3dimethylamino)propylidene-12H-dibenzo d,g! 1,3!dioxocine

2-Methyl-12-(3-(4methyl-1-piperazinyl)propylidene)-12H-dibenzo d,g!1,3!dioxocine

2-Chloro12-(3-(4methyl-1-piperazinyl)propylidene)-12H-dibenzo d,g!1,3!dioxocine

3-Chloro-12-(3-(4-methyl-1-piperazinyl)propylidene)-12H-dibenzo d,g!1,3!dioxocine

1-(3-(12H-Dibenzo d,g!1,3!dioxocine-12-ylidene)propyl)-3-piperidinecarboxylic acid ethyl ester

1-(3-(12H-Dibenzo d,g!1,3!dioxocin-12-ylidene)propyl)-3-piperidinecarboxylic acid

or a pharmaceutically acceptable salt thereof.

As used herein, the term "patient" includes any mammal which couldbenefit from treatment of neurogenic pain or inflammation or insulinresistance in NIDDM. The term particularly refers to a human patient,but is not intended to be so limited.

It has been demonstrated that the novel compounds of formula I inhibitneurogenic inflammation which involves the release of neuropeptides fromperipheral and central endings of sensory C-fibres. Experimentally thiscan be demonstrated in animal models of formalin induced pain or pawoedema (Wheeler and Cowan, Agents Actions 1991, 34, 264-269) in whichthe novel compounds of formula I exhibit a potent inhibitory effect.Compounds of formula I may be used to treat all painful, hyperalgesicand/or inflammatory conditions in which C-fibers play apathophysiological role by eliciting neurogenic pain or inflammation,i.e.:

Acutely painful conditions exemplified by migraine, postoperative pain,burns, bruises, post-herpetic pain (Zoster) and pain as it is generallyassociated with acute inflammation; chronic, painful and/or inflammatoryconditions exemplified by various types of neuropathy (diabetic,post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis,gout, in- flammatory bowel disease, prostatitis, cancer pain, chronicheadache, coughing, asthma, chronic pancreatitis, inflammatory skindisease including psoriasis and autoimmune dermatoses, osteoporoticpain.

Further, it has been demonstrated that the compounds of general formulaI improves the glucose tolerance in diabetic ob/ob mice and that thismay result from the reduced release of CGRP from peripheral nervousendings. Hence the compounds of general formula I may be used in thetreatment of NIDDM as well as ageing-associated obesity. Experimentallythis has been demonstrated by the subcutaneous administration of glucoseinto ob/ob mice with or without previous oral treatment with a compoundof general formula I.

The compounds of formula I may be prepared by the following method:##STR3## A compound of formula II wherein R¹, R², R³,A, and Y are asdefined above and W is a suitable leaving group such as halogen,p-toluene sulphonate or mesylate may be reacted with an azaheterocycliccompound of formula III wherein Z is as defined above. This alkylationreaction may be carried out in a solvent such as acetone, dibutylether,2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofurnan (THF)or toluene in the presence of a base e.g. sodium hydride and a catalyst,e.g. an alkali metal iodide at a temperature up to reflux temperaturefor the solvent used for e.g. 1 to 120 h. If esters have been preparedin which R¹⁵ is alkoxy, compounds of formula I wherein R¹⁵ is OH may beprepared by hydrolysis of the ester group, preferably at roomtemperature in a mixture of an aqueous alkali metal hydroxide solutionand an alcohol such as methanol or ethanol, for example, for about 0.5to 6 h.

Compounds of formula II and III may readily be prepared by methodsfamiliar to those saled in the art.

Under certain circumstances it may be necessary to protect theintermediates used in the above methods e.g. a compound of formula mwith suitable protecting groups. The carboxylic acid group can, forexample, be esterified. Intoduction and removal of such groups isdecribed in "Protective Groups in Organic Chemistry" J. F. W. McOmie ed.(New York, 1973).

Pharmacological Methods

I. Formalin induced pain or paw oedema

Values for in vivo inhibition of formalin induced pain or oedema for thecompounds of the present invention were assessed in mice essentially bythe method of Wheeler-Aceto and Cowan (Agents Action 1991, 34, 265-269).

About 20 g NMRI female mice were injected 20 ml 1% formalin into theleft hind paws The animals were then placed on a heated (31° C.) table,and the pain response was scored. After 1 h they were killed and bled.Left and right hind paws were removed and the weight difference betweenthe paws was used as indication of the oedema response of the formalininjected paw.

II. Histamine induced paw oedema

Values for in vivo inhibition of histaine induced oedema for thecompounds of the present invention were assessed in rats essentially asdescribed by Amann et al. (Europ. J. Pharmacol. 30 279, 227-231, 1995).

In brief 250-300 g male Sprague-Dawley rats were anaesthed withpentobarbital sodium, and placed on a 32 degree heated table. Tenminutes later histamine (50 microliter, 3 mg/ml) was injected in theright hind paw and 20 minutes hereafter the paw swelling was determinedby water plethysmography (Ugo Basile). Test compounds were administeredintraperitoneally at 15 minutes before the anesthetics.

                  TABLE 1                                                         ______________________________________                                        Inhibition of histamine induced oedema at 1 mg/kg                             Example no.  % oedema inhibition                                              ______________________________________                                        2            52                                                               3            33                                                               ______________________________________                                    

III. Reduced release of CGRP

ob/ob female mice, 16 weeks of age, where injected glucose (2g/kg)subcutaneously. At times hereafter blood glucose was determined in tailvenous blood by the glucose oxidase method. At the end of the study theanimals were decapitated and trunk blood collected. Immunoreactive CGRPwas determined in plasma by radio-immuno-assay. Two groups of animalswere used. The one group was vehicle treated, whereas the other groupreceived a compound of formula I via drinking water (100 mg/l) for fivedays before the test.

For the above indications the dosage will vary depending on the compoundof formula I employed, on the mode of administration and on the therapydesired. However, in general, satisfactory results are obtained with adosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mgto about 500 mg of compounds of formula I, conveniently given from 1 to5 times daily, optionally in sustained release form. Usually, dosageforms suitable for oral administration comprise from about 0.5 mg toabout 1000 mg, preferably from about 1 mg to about 500 mg of thecompounds of formula I admixed with a pharmaceutical carrier or diluent.

The compounds of formula I may be administered in a pharmaceuticallyacceptable acid addition salt form or where possible as a metal or alower alkylammonium salt. Such salt forms exhibit approximately the sameorder of activity as the free base forms.

This invention also relates to pharmaceutical compositions comprising acompound of formula I or a pharmaceutically acceptable salt thereof and,usually, such compositions also contain a pharmaceutical carrier ordiluent. The compositions containing the compounds of this invention maybe prepared by conventional techniques and appear in conventional forms,for example capsules, tablets, solutions or suspensions.

The pharmaceutical carrier employed may be a conventional solid orliquid carrier. Examples of solid carriers are lactose, terra alba,sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate andstearic acid. Examples of liquid carriers are syrup, peanut oil, oliveoil and water.

Similarly, the carrier or diluent may include any time delay materialknown to the art, such as glyceryl monostearate or glyceryl distearate,alone or mixed with a wax.

If a solid carrier for oral administration is used, the preparation canbe tabletted, placed in a hard gelatine capsule in powder or pellet formor it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will usually be from about 25 mg to about 1g. If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non- aqueous liquid suspension or solution.

Generally, the compounds of this invention are dispensed in unit dosageform comprising 50-200 mg of active ingredient in or together with apharmaceutically acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is 1-500 mg/day,e.g. about 100 mg per dose, when administered to patients, e.g. humans,as a drug.

A typical tablet which may be prepared by conventional tablettingtechniques contains

    ______________________________________                                        Core:                                                                         Active compound       100 mg                                                  (as free compound or salt thereof)                                            Colloidal silicon dioxide (Aerosil ®)                                                           1.5 mg                                                  Cellulose, microcryst. (Avicel ®)                                                                70 mg                                                  Modified cellulose gum (Ac-Di-Sol ®)                                                            7.5 mg                                                  Magnesium stearate                                                            Coating:                                                                      HPMC             approx.    9 mg                                              *Mywacett ® 9-40 T                                                                         approx.  0.9 mg                                              ______________________________________                                         *Acylated monoglyceride used as plasticizer for film coating.            

The route of administration may be any route which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral or parenteral e.g. rectal, transdermal,subcutaneous, intranasal, intramuscular, topical, intravenous,intraurethral, ophthalmic solution or an ointment, the oral route beingpreferred.

EXAMPLES

The process for preparing compounds of formula I and preparationscontaining them is further illustrated in the following examples, which,however, are not to be construed as limiting.

Hereinafter, TLC is thin layer chromatography and CDCl₃ is deuteriochloroform and DMSO-d₆ is hexadeuterio dimethylsulfoxide. The structuresof the compounds-are confirmed by either elemental analysis or NMR,where peaks assigned to characteristic protons in the title compoundsare presented where appropriate. ¹ H-NMR shifts (δ_(H)) are given inparts per million (PM). M.p. is melting point and is given in ° C. andis not corrected. Column chromatography was carried out using thetechnique described by W. C. Still et al, J. Org. Chem. (1978), 43,2923-2925 on Merck silica gel 60 (Art. 9385). Compounds used as startingmaterials are either known compounds or compounds which can readily beprepared by methods known per se.

EXAMPLE 1

1-(3-(12H-Dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acidhydrochloride ##STR4## 2,2'-Dihydroxybenzophenone (10.0 g, 46.7 mmol)and diiodomethane (13.1 g, 49 mmol) was dissolved in drydimethylformamide (180 ml). Dried, finely powdered potassium carbonate(9.2 g, 66.7 mmol) was added, and the mixture was heated at 105 ° C. for16 h. After cooling to room temperature the reaction mixture was pouredinto ice water (500 ml). The precipitate was collected by filtrationafter 0.5 h, washed with water on the filter and dissolved in a mixtureof ethanol (80 ml) and 4 N sodium hydroxide (20 ml). The solution wasstirred at reflux temperature for 1 h, cooled and diluted with water(300 ml). The formed crystalline precipitate was filtered off, washedwith water (50 ml) and dried in vacuo, affording 12H-dibenzo d,g!1,3!dioxocin-2-one as a solid (9.5 g, 90% yield).

M.p. 93°-95° C.

A solution of cyclopropylmagnesium bromide in dry tetrahydrofuran(prepared from cyclopropylbromide (24.2 g, 0.2 mol), magnesium turnings(4.86 g, 0.2 mol) and dry tetrahydrofuran (70 ml) was placed under anatmosphere of nitrogen. A solution of- the above ketone (9.05 g, 40mmol) in dry tetrahydrofuran (50 ml) was added dropwise. The reactionmixture was stirred at 40° C. for 1.5 h, cooled and added to an ice-cldmixture of saturated ammonium chloride (400 ml) and ether (200 ml). Theorganic layer was separated, the aqueous phase was extracted with ether(50 ml), the combined organic extracts were washed with water (2 ×100ml) and brine (50 ml), dried over MgSO₄, evaporated in vacuo andstripped with toluene (2 ×25 ml) to furnish 11.2 g12-cyclopropyl-12H-dibenzo d,g! 1,3!dioxocin-12-ol .

¹ H NMR (200 MHz, CDCl₃):δ0.50 (d, 2H); 0.75 (d, 2H); 2.00 (m, 1H); 5.14(s, 2H); 6.9-7.4 (m, 6H); 7.81 (d, 2H).

To a solution of the above alcohol (6.21 g, 22 mmol) in drydichloromethane (225 ml) trimethylsilylbromosilane (3.71 g, 24.2 mmol)was added. The reaction mixture was stirred at room temperature for 1 hand poured on an ice-cold saturated sodium hydrogencarbonate solution(75 ml). The organic phase was separated, washed with icewater (2 ×75ml) and brine (75 ml), dried over MgSO₄ and evaporated in vacuo, whichafforded 7.95 g of crude 12-(3-bromo-l-propylidene)-12H-dibenzo d,g!1,3!dioxocine, which was used in the next step without furtherpurification.

A mixture of the above crude bromide (1.83 g, 5.5 mmol), ethyl3-piperidinecarboxylate (0.865 g, 5.5 mmol), dried potassium carbonate(2.28 g, 16.5 mmol), sodium iodide (0.82 g, 5.5 mmol) and 2-butanone (25ml) was heated at reflux temperature for 3 h. After cooling to roomtemperature, diethyl ether (50 ml) and water (50 ml) was added to thereaction mixture. The organic layer was separated, washed with water(2×50 ml) and made acidic by addition of 2 N hydrochloric acid. Theaqueous layer was separated and the organic phase was extracted twicewith water (50 ml). The combined aqueous extracts were adjusted to pH8.5 with a saturated sodium bicarbonate solution and extracted withdichloromethane (2×25 ml). The organic extract was washed with water (50ml) dried over MgSO₄ and evaporated in vacuo, which afforded1-(3-(12H-dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid ethylester as a foam (1.66 g, 74%).

The above ester (1.66 g, 4.0 mmol) was dissolved in ethanol (20 ml) and2 N sodium hydroxide (6.6 ml, 13.2 mmol) was added. The mixture wasstirred at room temperature for 1.5 h. The ethanol was evaporated invacuo and the remainder was diluted with water (25 ml). 1 N Hydrochloricacid (17.6 ml) was added and the solution was washed with diethyl ether(25 ml). The aqueous phase was extracted with dichloromethane (3×30 ml).The combined organic extracts were dried over MgSO₄ and evaporated invacuo to afford 1.1 g of the title compound as a foam, which wastriturated with ethyl acetate, filtered off and dried.

M.p. 190°-92° C., decomp.

Calculated for C₂₃ H₂₅ NO₄, HCl, 0.25 C₄ H₈ O₂ :

C, 65.82%; H, 6.44%; N, 3.20%; Found:

C, 65.76%; H, 6.58%; N, 3.05%.

EXAMPLE 2

(R)-1-(3-(12H-Dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acidhydrochloride ##STR5## A mixture of12-(3-bromo-1-propylidene)12H-dibenzo d,g! 1,3!dioxocine (7.90 g, 22mmol, prepared as described in example 1, (R)-3-piperidinecarboxylicacid ethyl ester (L)-tartrate (6.60 g, 22 mmol), dry potassium carbonate(12.2 g, 88 mmol), sodium iodide (3.5 g, 22 mmol) and 2-butanone (100ml) was heated at reflux temperature for 16 h. After cooling to roomtemperature, diethyl ether (100 ml) and water (100 ml) was added. Theorganic layer was separated, washed with water (2×50 ml) and made acidicby addition of 2 N hydrochloric acid. The aqueous layer was separatedand the organic phase was extracted twice with water (50 ml).

The combined aqueous extracts were adjusted to pH 8.5 with a satatedsodium bicarbonate solution and extractd with dichloromethane (2×25 ml).The organic extract was washed with water (50 ml) dried over MgS₄ andevaporated in vacuo. The resulting residue (6.21 g) was purified bychromatography on silica gel using a mixture of toluene and ethyl ac eas eluent to give (R)-1-(3-(12H-dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-3-piperecaiboxylic acid ethyl esteras an oil (3.96 g, 41%).

The above ester (3.06 g, 7.5 mmol) was dissolved in ethanol (40 ml) and2 N sodium hydroxide (12.4 ml, 24.8 mmol) was added. The mixture was soat room temperature for 1.0 h. The ethanol was evaporated in vacuo andthe remainder was diluted with water (25 ml). The pH was adjusted to 6by addition of I N hydrochloric acid and the solution was washed withdiethyl ether (25 ml). The aqueous phase was ext with dichloroinethane(3×30 ml). The combined organic extracts were dned over MgSO₄ andevapoxrad in vacuo to afford 2.75 g of a foam, which was dissolved inetrahydrofuran (75 ml). Dropwise addition of excess hydrogen chloride inether afforded the tid compound as crystals, which were filtered off anddried (2.65 g, 85%).

M.p. 227°-228 ° C., decomp.

Calculated for C₂₃ H₂₅ NO₄, HCl:

C, 66.42%; H, 6.30%; N, 3.37%; Found:

C, 66.50%; H, 6.61%; N, 3.14%.

EXAMPLE 3

(R)-1-(3-(12H-Dibenzo d,g!1,3!doxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid ethylester hydrochloride

(R)-1-(3-(12H-Dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid ethylester (0.86 g, 2.1 mmol, prepared as descibed in example 2) wasdissolved in tetahydrofuran (10 ml) and a 2.6 N solution of hydrogenchloride in ether (0.97 ml, 2.52 mmol) was added dropwise. The solutionwas evaporated in vacuo and the remainder was treated wit ether (20 ml).The preipitate was filtered off, washed with ether and dried in vacuo,affording the title compound as a powder.

Calculated for C₂₅ H₂₉ NO₄,HCl, 0.5 H₂ O:

C, 66.29%; H, 6.90%; N, 3.09%; Found:

C, 65.97%; H, 7.03%; N, 2.87%.

EXAMPLE 4

1-(3-(12H-Dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-4-pipenrdinecaboxylic acidhydrochloride ##STR6## A mixture of12-(3-bromo-1-propylidene)-12H-dibenzo d,g! 1,3!dioxocine (4.0 g, 12mmol, prepared as described in example 1), 4-piperidinecarboxylic acidethyl ester (1.9 g, 12 mmol), anhydrous potassium carbonate (5.0 g) andsodium iodide (0.2 g) in N,N-dimethylformamide (40 ml) was heated at60°-70° C. for 5 h. After cooling, the inorganic salts were filtered offand washed with benzene (40 ml), and the filtrate was diluted withadditional benzene (120 ml). The benzene solution was washed with water(3×50 ml), dried over MgSO₄ and evaporated in vacuo. The oily residue(4.8 g) was purified by chromatography on silica gel using a mixture ofbenzene and ethyl acetate as eluent to give 1-(3-(12H-dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)4-piperidinecarboxylic acid ethylester as an oil (2.3 g, 47%).

The above ester (2.30 g, 5.6 mmol) was dissolved in ethanol (30 nl), a20% solution of sodium hydroxide (3.5 ml) was added and the mixture wasstirred at room temperature for 7 h. The solution was diluted withdichloromehane (240 ml) and acidified with concentrated hydrochloricacid (3 ml). The mixture was washed with water (10 ml), the organicphase was dried over MgSO₄ and evaporated in vacuo. The solid residuewas washed with acetone, filtered off and dried in vacuo, affording theLtile compound (1. 8 g, 73%).

M.p. 239-245° C.

Calculated for C₂₃ H₂₅ NO₄, HCl, 0.5 C₂ H₅ OH:

C, 65.67%; H, 6.66%; Cl, 8.08%; N, 3.19%; Found:

C, 65.51%; H, 6.35%; Cl, 8.78%; N, 3.27%.

EXAMPLE 5

(R)-1-(3-(2,10-Dichloro- 12H-dibenzo d,g!1,3!-dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acidhydrochloride ##STR7## 2,2'-Dihydroxy-5,5'-dichlorobenzophenone (12.1 g,0.042 mol, prepared similarly as described in Journal of the AmericanChemical Society 77, 543 (1955)) and diiodomethane (11.9 g, 0.044 mol)were dissolved in dry N,N-dimethylformamide (226 ml). Dried and powderedpotassium carbonate (8.3 g) was added and the mixture was heated at 105°C. for 5 h and left overnight at room temperature. The reaction mixturewas poured on ice (220 g). The precipitate was collected by filtrationafter 0.5 h and dissolved in diethyl ether (500 ml). The organic layerwas washed with 5% sodium hydroxide (50 ml), dried over MgSO₄ andevaporated in vacuo, affording 12 g (96%) of 2,10-dichloro-12H-dibenzod,g! 1,3!-dioxocin-12-one as a solid.

To a solution of cyclopropylmagnesium bromide in dry tetrahydrofuran(prepared from cyclopropylbromide (15.7 g, 0.130 mol), magnesiumturnings (3.15 g, 0.130 mol) and dry tetrahydrofuran (45 ml)), asolution of the above ketone (7.65 g, 0.026 mol) in dry tetrahydrofuran(30 ml) was added over 5 minutes with cooling. The reaction mixture wasstirred at 38°-42° C. for 3 h, cooled in an ice-bath, and a mixture ofsaturated ammonium chloride (260 ml) and diethyl ether (130 ml) wasadded. The reaction mixture was filtered, the organic layer wasseparated, the aqueous phase was extracted with diethyl ether (35 ml).The combined organic extracts were washed with water (2×70 ml) and brine(70 ml), dried over MgSO₄ and evaporated in vacuo. The crude product waspurified by column chromatography on silica gel (140 g) using benzene aseluent. This afforded 8.75 g (98%) of2,10-dichloro12-cyclopropyl-12H-dibenzo d,g! 1,3!dioxocin-12-ol as asolid. To a solution of the above alcohol (8.75 g, 0.027 mol) in drydichloromethane (245 ml) trimethylsilyl bromiide (4.02 g, 0.026 mol) wasadded. The reaction mixture was stirred at room temperature for 1 h andpoured on an ice cold saturated sodium hydrogencarbonate solution (80ml). The organic phase was separated, washed with water (2×80 ml) andbrine (80 ml), dried over MgSO₄ and evaporated in vacuo. This afforded9.12 g of an oil, which was purified by column chromatography on silicagel (250 g) using a mixture of cyclohexane and benzene (3.1) as eluent.This yielded 6.61 g (62%) of2,10-dichloro-12-(3-bromo-1-propylidene)-12H-dibenzo d,g! 1,3!dioxocineas an oil which crystllized on standing.

A mixture of the above bromide (3.0 g, 0.0075 mol),(R)-3-piperidinecarboxylic acid ethyl ester tartate (3.45 g, 0.0112mol), dried potassium carbonate (10.35 g, 0.075 mol) andN,N-dimethylformamide (42 Ml) was heated at 60° C. for 12 h. Aftercooling to room temperature, water (150 ml) and benzene (75 ml) wereadded. The organic layer was separated, washed with water (3×60 ml),dried over MgSO₄ and evaporated in vacuo. The crude oil was purified bycolumn chromatography on silica gel (65 g) using chloroform as eluent.This afforded 1.44 g (40%) of (R)-1-(3-(2,10-dichloro-12H-dibenzo d,g!1,3!- dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid ethylester as an oil.

The above ester (1.44 g, 0.003 mol) was dissolved in ethanol (25 ml) and4 N sodium hydroxide (3.36 ml, 0.013 mol) was added. The mixture wasleft at room temperature overnight. Concentrated hydrochloric acid (1.68ml), followed by dichloromedmane (170 ml) were added, the organic layerwas separated, dried over MgSO₄ and evaporated. Evaporation was repeatedwith dichloromethane (120 ml) and acetone (20 ml). The oily residue wasdissolved in acetone (10 ml), yielding, after 12 h at room temperature,0.54 g (37%) of the title compound as crystals.

¹ H NMR (250 MHz, DMSO-d₆): δ_(H) 7.49 (d, J=2.5 Hz, 1 H); 7.32 (dd,J=2.5 Hz and 8.8 Hz, 1 H);7.26 (dd, J=2.5 Hz and 8.8 Hz, 1 H); 7,19 (d,J=2.5 Hz, 1 H); 7.09 (d, J=8.8 Hz, 1 H); 6.97 (d, J=8.8 Hz, 1 H); 6.09(t, J=7.2 Hz, 1 H); 5.84 (s, 2 H); 2.43 (q, J=7.2 Hz, 2 H); 3.15 (t,J=7.2 Hz).

Calculated for C₂₃ H₂₃ Cl₂ NO₂, HCl, 0.5 C₃ H₆ O:

C, 57.26%; H, 5.30%; N, 2.73%; Cl, 20.70%; Found:

C, 56.95%; H, 5.31%; N, 2.53%; Cl, 20.75%.

EXAMPLE 6

1-(3-(12H-Dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-3-pyrrolidineacetic acidhydrochloride ##STR8## A mixture of12-(3-bromo-1-propylidene)-12H-dibenzo d,g! 1,3!dioxocine (500 g, 15mmol, prepared as described in example 1), methyl 3-pyrrolidineacetateacetate (3.04 g, 15 mmol), potassium carbonate (6.2 g, 45 mmol) andpotassium iodide (2.23 g, 13 mmol) in 2-butanone (70 ml) was heated atreflux temperature for 5 h. The readon mixture was cooled and water (140ml) and ether (140 ml) were added. The mixture was vigorously stirredfor 5 minutes, the organic layer was separated, washed with water (2×50ml) and dried over MgSO₄. The solvent was evaporated in vacuo and theresidue (4.34 g) was submitted to column chromatography on silica gel(100 g) using a mixture of dichloro-methane and methanol (10:1) aseluent. This afforded l.05 g of 1-(3-(12H-dibenzo d,g!-1,3!dioxocin-12-ylidene)-1-propyl)-3-pyrrolidineacetic acid methylester.

To a solution of the above ester (0.85 g, 2.1 mmol) in ethanol (16 ml),20% sodium hydroxide (1.3 ml) was added, the mixture was stirred at roomtemperature for 2 h and left to stand overnight. The solution was pouredinto dichloromethane (100 ml), cooled in an ice bath, acidified with 2 Nhydrochloric acid and stirred for 10 minutes. Additional water was added(5 ml). The organic layer was dried over MgSO₄, parally decolorized withactive charcoal and evaporated in vacuo. The hydrochloride of the titlecompound separated as an amorphous hygroscopic solid (0.64 g, 77%).

M.p. 70°-90° C.

¹ H NMR (250 MHz, CDCl₃): δ_(H) 7.15 (m, 8 H); 5.95 (t, J=7.2 Hz, 1H);5.85 (s, 2 H); 3.36-1.51 (bm, 13H).

Calculated for C₂₃ H₂₅ NO₄, HCl, 0.5 C₂ H₆ O:

C, 65.67%; H, 6.66%; N, 3.19%; Found:

C, 65.79%; H, 6.59%; N, 3.21%.

EXAMPLE 7

1-(3-(2,10-Dichloro-12H-dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-3-pyrrolidineacetic acidhydrochloride ##STR9## A mixture of2,10-dichloro-12-(3-bromo-1-propylidene)-12H-dibenzo d,g! 1,3!-dioxocine(4.0 g, 0.01 mol, prepared as described in example 5),3-pyrrolidinacetic acid methyl ester acetate (2.23 g, 0.011 mol),potassium carbonate (4.5 g, 0.0325 mol) and sodium iodide (1.1 g, 7.3mmol) in 2-butanone (60 ml) was heated at reflux temperature for 6 h.After cooling to room temperature the reaction mixture was diluted withacetone, filtered and evaporated in vacuo. The crude product waspurified by column chromatography on silica gel (200 g), using a mixtureof chloroform (95 %) and ethanol (5%) as eluent This afforded 0.8 g(17.3%) of 1-(3-(2,10-dichloro-12H-dibenzo d,g!1,3!dioxocin-12-ylidine)-1-propyl)-3-pyrrolidineacetic acid methyl esteras an oil.

To the above ester (0.8 g, 1.78 mmol) in ethanol (11.6 ml) a solution ofsodium hydroxide (0.288 g) in water (1.08 ml) was added and the reactionmixture was stirred at room temperature for 16 h. Concentratedhydrochloric acid (1.08 ml) was added followed by dichloromethane (80ml). After stirring for 10 minutes the organic layer was separated,dried over MgSO₄ and evaporated in vacuo. The residue was dissolved inacetone (20 ml) and evaporated. The re-evaporation with acetone wasrepeated twice. The residue was again dissolved in acetone (40 ml) andleft at 0° C. for 4 h. This afforded 300 mg (36%) of the title compoundas a solid.

M.p. 183°-193° C., decomp.

Calculated for C₂₃ H₂₃ Cl₂ NO₄, HCl:

C, 56.98%; H, 4.99%; N, 2.89%; Found:

C, 56.92%; H,5.02%; N, 3.16%.

EXAMPLE 8

(R)-1-(2-(12H-Dibenzo d,g!1,3!dioxocin-12-yloxy)-1-ethyl)-3-piperidinecarboxylic acid acetate##STR10## To a suspension of 12H-dibenzo d,g! 1,3!dioxocin-12-one (9.05g, 40 mmol) in ethanol (140 ml) a solution of sodium borohydride (0.8 g,21 mmol) in water (5 ml containing 2 drops of 10% sodium hydroxide) wasadded dropwise at 40° C. and the reaction mixture was stirred at 70° C.for 5 h. Additional solid sodium borohydride (1.0 g, 2.6 mmol) was addedin small portions and the reaction mixture was heated to 70° C. for 2 h.The cloudy solution was filtered and the solvent removed in vacuo.Toluene (150 ml) and water (80 ml) were added, the layers wereseparated, and the aqueous layer was extracted with toluene (50 ml). Thecombined toluene extracts were washed with water (50 ml), dried overMgSO₄ and evaporated in vacuo. The residue (9.03 g), which crystallisedafter standing was triturated with cyclohexane and filtered off, and thehereby obtained 12H-dibenzo- d,g! 1,3!dioxocin-12-ol was used in nextstep without further purification.

M.p. 80°-90° C.

To a solution of the above alcohol (5.0 g, 22 mmol) in benzene (85 ml)triethylamine (5.5 g, 54 mmol) was added, and a solution ofmethanesulfonyl chloride (3.2 g, 28 mmol) in benzene (25 ml) was addeddropwise at 15°-20° C. over 20 minutes under cooling on a cold waterbath. After addition, the reaction mixture was stirred for 2 h at roomtemperature. Water (35 ml) was added, and the organic layer wasseparated, washed with water (25 ml), dried over MgSO₄ and evaporated invacuo. To the residual oil (5.8 g), anhydrous potassium carbonate (8.6g, 62 mmol) and 2-bromoethanol (13.6 ml, 191 mmol) were added. Thereacton mixture was stirred for 17 h at room temperature, diluted withdichloromethane (60 ml), filtered and evaporated in vacuo. Solid12-(2-bromoethoxy)-12H-dibenzo d,g! 1,3!dioxocine (5.0 g, 68%) separatedfrom the residue after standing at room temperature and was filtered offand washed with petroleum ether.

M.p. 112°-114° C.

A solution of the above bromide (1.7 g, 5 mmol),(R)-3-piperidinecarboxylic acid ethyl ester tartrate (2.1 g, 6.7 mmol)and potassium carbonate (1.1 g, 8 mmol) was stirred for 22 h at roomtemperature. Inorganic salts were filtered off, and the filtrate wasdiluted with water (130 ml) and extracted with diethyl ether (2×40 ml).The organic extracts were washed with water (2×20 ml), dried over MgSO₄and evaporated in vacuo. The oily residue, crude (R)-1-(2-(12H-dibenzod,g! 1,3!dioxocin-12-yloxy)-1-ethyl)-3-piperidinecarboxylic acid ethylester was used in the next step without further purification.

The above ester (1.6 g, 3.9 mmol) was dissolved in ethanol (16 ml) and20% sodium hydroxide (2.1 ml) was added. The reaction mixture was siredat room temperature for 18 h, poured into dichloromethane (320 ml) andacidified with concentrated acetic acid (5.3 ml). The organic phase waswashed with water (50 ml), dried over MgSO₄ and evaporated in vacuo. Theoily residue was revaporated twice with benzene then trturated withacetone to give crystals of the le compound (0.96 g, 55%).

M.p. 12°-28° C.

Calculated for C₂₄ H₂₉ NO₇ :

C, 65.00%; H, 6.59%; N, 3.16%. Found:

C, 65.21%; H, 6.70%; N, 3.06%.

EXAMPLE 9

(R)-1-(2-(2, 10-Dichloro-12H-dibenzo d,g!1,3!dioxocin-12-yloxy)-1-ethyl)-3-piperidinecarboxylic acidhydrochloride ##STR11## Bis-(5-chloro-2-hydroxyphenyl)methane (25.0 g,92.9 mmol) was dissolved in N,N-dimethyl formamide (350 ml), anddiiodomethane (7.8 ml, 97.5 mmol) and potassium carbonate (18.6 g, 135mmol) were added. The mixture was heated to 105° C. overnight. Aftercooling, the mixture was poured into icewater (1200 ml). A precipitatewas formed immediately. After stirring for 30 minutes, the solid wasfiltered off and washed with a small amount of water. The solid wassuspended in a mixture (80:20) of ethanol and 4 M sodium hydroxide, andthe resulting mixture was heated at 80° C. for 1 h. After cooling, themixture was poured into water (600 ml), and the precipitate was filteredoff. After drying, this afforded 2,10-dichloro-12H-dibenzo d,g!1,3!-dioxocine (24.8 g, 95%), which was used for further reactionwithout purification.

The above dioxocine (7.7 g, 27 mmol) and N-bromosuccinimide (5.4 g, 30mmol) were suspended in tetrachloromethane (100 ml).Azobisisobutyronitrile (50 mg) was added and the mixture was heated atreflux temperature. During the first.7 h, every second hour, portions ofmore azobisisobutyronitrile (50 mg) were added. Heating was continuedovernight. Two additional portions of azobisisobutyronitrile (50 mg)were then added and heating at reflux temperature was continued for 24 hin total. After cooling, the reaction mixture was filtered andevaporated. Dichloromethane (10 ml) and diethyl ether (15 ml) were addedand the solid was filtered off, affording after drying12-bromo-2,10-dichloro-12H-dibenzo d,g! 1,3!dioxocine (3.37g, 11%).

The above bromide (3.37 g, 9.36 mmol) was mixed with 2-bromoethanol (8.0ml, 110 mmol) and potassium carbonate (3.9 g, 28 mmol). The mixture wasstirred for 1 h at room temperature. Dichloromethane (10 ml) was addedto dilute the mixture, and stirring was continued overnight at roomtemperature. The mixture was heated at 120° C. for 24 h. After cooling,the mixture was evaporated, and ethyl acetate (100 ml) and water (100mnl) were added. The phases were separated and the organic phase waswashed with water (100 ml). The combined aqueous phases were extractedwith ethyl acetate (100 ml). The organic extracts were dried (MgSO₄) andevaporated to give crude 12-(2-bromoethoxy)-2,10-dichloro-12H-dibenzod,g! 1,3!dioxocine (4.34 g). The product was used for further reactionwithout purification.

The above bromoethoxy compound (4.25 g, 10.5 mmol) was suspended indimethyl sulfoxide (50 ml). (R)-3-Piperidinecarboxylic acid ethyl estertartrate (4.1 g, 13.7 mmol) and potassium carbonate (3.2 g, 23 mmol)were added. The reaction mixture was stirred at 50° C. overnight. Aftercooling and filtration, water (250 ml) was added and the mixture wasextracted with diethyl ether (2×100 ml). The organic extracts werewashed with water (75 ml), dried (MgSO₄) and evaporated. The residualoil was purified by column chromatography on silica gel (600 ml) using amixture of heptane and ethyl acetate (2:1) as eluent. This afforded(R)-1-(2-(2,10-dichloro-12H-dibenzo d,g!1,3!dioxocin-12-yloxy)-1-ethyl)-3-piperidinecarboxylic acid ethyl ester(2.0 g, 40%) as an oil.

The above ester (0.78 g, 1.62 mmol), dissolved in a solution of sodiumhydroxide (0.54 g, 13.5 mmol) in ethanol (40 ml) and water (5 ml) wasstirred at room temperature for 3.5 h. The pH of the mixture wasadjusted to 4 by addition of 1 N hydrochloric acid (14 ml). The mixturewas extracted with dichloromethane (2×60 ml), the combined organicphases were washed with brine (75 ml), dried over MgSO₄ and the solventwas removed in vacuo. The residue was stirred with acetone (10 ml) for2.5 h, the solid product was filtered off and dried, affording the titlecompound (0.56 g, 71%).

M.p. 218°-220° C.

Calculated for C₂₂ H₂₃ Cl₂ NO₅, HCl:

C, 54.06%; H, 4.95%; N, 2.87%; Found:

C, 53.9%; H, 4.8%; N, 2.6%.

EXAMPLE 10

(R)-1-(3-(2-Chloro-12H-dibenzo d,g!1,3,6!dioxazocin-12-yl)-1-propyl)-3-piperidinecarboxylic acidhydrochloride ##STR12##

A suspension of 2-chloro12H-dibenzo d,g! 1,3,6!dioxazcine (10.65 g, 43mmol prepared as described in Journal of Molecular Structures, 131,1985, 131-140) and 3chloropropionyl chloride (6.55 g, 51.6 mmol) in drytoluene (100 ml) was heated at reflux temperature for 5 h. After coolingto room tempeature, the reaction mixture was washed with a satatedsolution of sodium bicarbonate (50 ml). The organic layer was dried(MgSO₄), and evaporated in vacuo, which afforded2-chloro-12-(3chloropropionyl)-12H-dibenzo d,g! 1,3,6!dioxazocine (12.9g, 88%).

A predried flask with lithium aluminium hydride (3.0 g, 79 mmol),suspended in dry tetrahydrofuran (80 ml), was cooled in an ice bath andconcentrated sulphuric acid (3.87 g, 39.5 minol) was added dropwise at arate to maintain a temperture <12° C. The solution was stirired at roomtemperature for 1.5 h. A solution of the above chloride (12.8 g, 37.8mmol) in dry tetrahydrofuran (80 ml) was added dropwise and sing wascontinued for 2 h. The readon was quenched by careful addition of ethylacetate (100 ml) followed by water (5.7 ml). Filtration of the mixtureand evaporation of the filtrate in vacuo afforded2-chloro-12-(3-chloropropyl)-12H-benzo d,g! 1,3,6!dioxazocine as a foam.

A mixture of the above crude chloride (1.14 g, 3.5 mmol),(R)-3-piperidinecarboxylic acid ethyl ester (L)-tartrate (1.05 g, 3.5mmol), dried potassium carbonate (1.94 g, 14 mmol), sodium iodide (0.53g, 3.5 mmol) and 2-butanone (15 ml) was heated at reflux temperature for60 h. The reaction mixture was filtered, the filtrate washed with2-butanone (10 ml) and the combined filtrates evaporated in vacuo. Thecrude product was purified by column chiomatography on silica gel usinga nature of ethyl acetate and heptane (1:3) contg triethylaine (2.5%) aseluent This afforded the product, (R)-1-(3-(2-chloro-12H-dibenzo d,g!1,3,6!dioxazocin-12-yl)-1-propyl)-3-piperddinexylic acid ethyl ester(0.77 g, 49%) as an oil.

The above ester (0.77 g, 1.73 mmol) was dissolved in ethanol (7.5 ml)and 2 N sodium hydroxide (2.86 ml, 5.71 mmol) was added. The mixture wasstirred at room temperature for 16 h. The ethanol was evaporated invacuo and the remainder was diluted with water (25 ml). pH was adjustedto 6 by addition of 6 N hydrochloric acid and the aqueous solution wasextracted with dichloromethane (3×15 ml). The combined organic extractswere dried over MgSO₄ and evaporated in vacuo. The remainder wasdissolved in tetrahydrofuran (15 ml) and 2.5 N hydrogen chloride inether (0.59 ml, 1.47 mmol) was added dropwise. Ether (30 ml) was addedand the mixture was stirred for 3 h, the precipitate was filtered offand dried, to afford 0.53 g (68%) of the title compound as a powder.

M.p. 177°-180° C.

Calculated for CH₂₅ H₂₅ ClN₂ O₄,HCl:

C, 58.28%; H, 5.78%; N, 6.18%; Found:

C, 58.3%; H, 5.9%; N, 6.1%.

EXAMPLE 11

1-(3-(12H-Dibenzo d,g!1,3,6!dioxazocin-12-yl)-1-propyl)-4-piperidinecarboxylic acidhydrochloride ##STR13## N-(2-Hydroxyphenyl)formamide (16.0 g, 130 mmol)was dissolved in 99.9% ethanol (65 ml). Sodium methoxide 7.0 g, 130mmol) was suspended in 99.9% ethanol (70 ml) and added dropwise over 30minutes. The resulting mixture was stirred for 30 minutes.1-Bromo-2-chloromethoxybenzene (26.1 g, 118 mmol, synthesis described inJ. Heterocycl. Chem., 11, 1974, 331-337) was added dropwise over 15minutes. The reaction mixture was stirred for 2.5 h at room temperature,heated at reflux temperature for 2 h, and stirred at room temperatureovernight. The mixture was filtered and evaporated. The residue wasdissolved in toluene (500 ml) and washed with a saturated sodiumcarbonate solution (2×200 ml). The organic phase was dried (MgSO₄) andevaporated. The residue was suspended in ethanol (40 ml), filtered andwashed with ethanol (3×10 ml). After drying, this afforded the product,N-(2-(2-bromophenoxymethoxy)phenyl)formamide (14.1 g, 37%).

The above formamide (6.8 g, 21 mmol) was suspended in Dowtherm (75 ml),and potassium carbonate (3.9 g, 28 mmol) was added, followed by copper(1.1 g, 17 mmol) and copper bromide (1.5 g, 11 mmol). The reactionmixture was heated at 180° C. overnight. After cooling, the mixture wasfiltered, and the filter cake was washed with dichloromethane. Dowthermand solvent was distilled off, and ethanol (200 ml) was added to theresidue, which was left overnight. 4 M Sodium hydroxide (14 ml) wasadded, and the mixture was heated at reflux temperature for 1 h. Aftercooling, the mixture was filtered and evaporated. The residue wassuspended in ethyl acetate (200 ml) and water (100 ml). The organicphase was washed with water (2×75 ml). The aqueous phases were extractedwith ethyl acetate (100 ml). The combined organic extracts wereevaporated. The residue was suspended in warn cyclohexane (100 ml), andleft cooling under stiring. The precipitated solid was filtered off,affording after drying the product 12H-dibenzo d,g! 1,3,6!dioxazocine(4.57 g, 50%).

The above dioxazocine (4.0 g, 19 mmol) was dissolved in dryN,N-dimethylformarnide (150 ml). Sodium hydride (1.13 g, 28 mmol, 60%dispersion in oil) was added in portions, and the resulting mixture wasstirred for 30 minutes at room temperature. 1-Bromo-3-chloropropane (4.6ml, 47 mmol) was slowly added dropwise, and the reaction mixture wasstirred at room temperature overnight. More sodium hydride (0.56 g, 14mmol) was added, and stirrng was continued for 6 h. More sodium hydride(0.56 g, 14 nunol) was added, and strring was continued overnight.Ammonium chloride (3.2 g) was added, and the mixture was stirred for 30minutes. Water was added (300 ml), and the mixture was extracted withdichloromethane (2 ×250 ml). The organic extracts were dried (MgSO₄) andevaporated. The residue was purified by column chromatography on silicagel using a mixture of heptane and ethyl acetate (6:1) as eluent. Thisafforded the product, 12-(3-chloropropyl)-12H-dibenzo d,g!1,3,6!dioxazocine (2.18 g, 40%).

The above chloride (1.0 g, 3.5 mmol) and potassium iodide (3.7 g, 22mmol) in methyl ethyl ketone (110 ml) was heated at reflux temperaturefor 4 h. 4-Piperidinecarboxylic acid ethyl ester (0.8 g, 5.2 mmol) wasdissolved in methyl ethyl ketone (5 ml) and added, followed by potassiumcarbonate (1.2 g, 8.6 mmol). The reaction mixture was heated at refluxtemperature for 48 h. After cooling, the mixture was filtered, thefilter cake was washed with methyl ethyl ketone, and the filtrate wasevaporated. The residual oil was purified by column chromatography onsilica gel (500 ml) using ethyl acetate as eluent. This afforded1-(3-(12H-dibenzo d,g!1,3,6!dioxazocin-12-yl)-1-propyl)-4-piperidinecarboxylic acid ethylester (0.80 g, 57%) as an oil.

The above ester (0.50 g, 1.22 mmol), dissolved in a solution of sodiumhydroxide (0.24 g, 6 mmol) in ethanol (30 ml) and water (3 ml) wasstirred at room temperature for 3 h. The pH of the mixture was adjustedto 3 by addition of 1 N hydrochloric acid (5 ml). The mixture wasextracted with dichloromethane (2×40 ml), the combined organic phaseswere washed with brine (50 ml), dried over MgSO₄ and the solvent wasremoved in vacuo. The residue was triturated with acetone (20 ml), thesolid product was filtered off and dried, affording the title compoundin quantitative yield (0.52 g).

M.p. 180°-187° C.

Calculated for C₂₂ H₂₆ N₂ O₄, HCl, 1.25 H₂ O:

C, 59.85%; H, 6.74%; N, 6.35%; Found:

C, 59.85%; H, 6.60%; N, 6.00%.

We claim:
 1. A compound of formula I ##STR14## wherein R¹ and R²independently are hydrogen, halogen, trifluoromethyl, hydroxy, C₁₋₆-alkyl or C₁₋₆ -alkoxy; andR³ is hydrogen or C₁₋₃ -alkyl; and A is C₁₋₃-alkylene; and Y is >CH-CH₂ -, >C=CH-, >CH-O-, or >C=N-, wherein onlythe underscored atom participates in the ring system; and Z is ##STR15##wherein n is 1 or 2; R¹¹ is hydrogen or C₁₋₆ -alkyl; R¹² is hydrogen,C₁₋₆ -alkyl, C₁₋₆ -alkoxy or phenyl optionally substituted with halogen,trifluoromethyl, hydroxy, C₁₋₆ -alkyl or C₁₋₆ -alkoxy; R¹³ is hydrogen,halogen, trifluoromethyl, hydroxy, C₁₋₆ alkyl or C₁₋₆ -alkoxy; R¹⁴ is-(CH₂)_(m) OH or -(CH₂)_(t) COR¹⁵ wherein m is 0, 1, 2, 3, 4, 5 or 6, tis 0 or 1, and R¹⁵ is -OH, NH₂, -NHOH or C₁₋₆ -alkoxy; and R¹⁶ is C₁₋₆-alkyl or -B-COR¹⁵, wherein B is C₁₋₆ -alkylene, C₂₋₆ -alkenylene orC₂₋₆ -alkynylene and R¹⁵ is the same as above; and . . . is a singlebond or a double bond; or a pharmaceutically acceptable salt thereof. 2.A compound according to claim 1 wherein R¹ and R² independently arehydrogen or halogen.
 3. A compound according to claim 1 wherein Yis >CH-O-.
 4. A compound according to claim 1 wherein Y is >C=CH-.
 5. Acompound according to claim 1 wherein Z is ##STR16##
 6. A compoundaccording to claim 5, wherein R¹⁴ is -(CH₂)_(t) COR¹⁵ wherein t is 0 or1 and wherein R¹⁵ is -OH.
 7. A compound according to claim 3 wherein Zis ##STR17##
 8. A compound according to claim 7, wherein R¹⁴ is-(CH₂)_(t) COR¹⁵ wherein t is 0 or 1 and wherein R¹⁵ is -OH.
 9. Acompound according to claim 4 wherein Z is ##STR18##
 10. A compoundaccording to claim 9, wherein R¹⁴ is -(CH₂)_(t) COR¹⁵ wherein t is 0 or1 and wherein R¹⁵ is -OH.
 11. A compound according to claim 1 whichis:1-(3-(12H-Dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid;(R)-1-(3-(12H-Dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid;(R)-1-(3-(12H-Dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid ethylester; 1-(3-(12H-Dibenzo d,g!1,3!dioxocin-12-ylidene)-1-propyl)-4-piperidinecarboxylic acid;(R)-1-(3-(2,10-Dichloro-12H-dibenzo d,g! 1,3!dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid; (R)-1-(2-(12H-Dibenzod,g! 1,3!dioxocin-12-yloxy)-1-ethyl)-3-piperidinecarboxylic acid;(R)-1-(2-(2,10-Dichloro-12H-dibenzo d,g!1,3!dioxocin-12-yloxy)-1-ethyl)-3-piperidinecarboxylic acid;1-(3-(12H-Dibenzo d,g!1,3!dioxocin-12-ylidene)propyl)-3-piperidinecarboxylic acid ethyl ester;or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising as active component a compound according to claim1 together with a pharmaceutically carrier or diluent.
 13. Thepharmaceutical composition according to claim 12, comprising between 0.5mg and 1000 mg of the compound.
 14. A method of treating neurogenicinflammation, migraine, diabetic neuropathy or rheumatoid arthritis in asubject in need of such treatment comprising administering to thesubject an effective amount of a compound according to claim
 1. 15. Amethod of treating insulin resistance in a subject in need of suchtreatment comprising administering to the subject an effective amount ofa compound according to claim
 1. 16. A method of treating neurogenicinflammation, migraine, diabetic neuropathy or rheumatoid arthritis in asubject in need of such treatment comprising administering to thesubject a pharmaceutical composition according to claim
 12. 17. A methodof treating insulin resistance in a subject in need of such treatmentcomprising administering to the subject a pharmaceutical compositionaccording to claim 12.